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Cardiomyocyte intercellular signalling increases oxidative stress and reprograms the global‐ and phospho‐proteome of cardiac fibroblasts

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journal contribution
posted on 2024-05-15, 00:42 authored by Bethany ClaridgeBethany Claridge, Alin RaiAlin Rai, Jarmon G Lees, Haoyun Fang, Shiang Y Lim, David GreeningDavid Greening

Pathological reprogramming of cardiomyocyte and fibroblast proteome landscapes drive the initiation and progression of cardiac fibrosis. Although the secretome of dysfunctional cardiomyocytes is emerging as an important driver of pathological fibroblast reprogramming, our understanding of the downstream molecular players remains limited. Here, we show that cardiac fibroblast activation (αSMA+) and oxidative stress mediated by the secretome of TGFβ‐stimulated cardiomyocytes is associated with a profound reprogramming of their proteome and phosphoproteome landscape. Within the fibroblast global proteome there was a striking dysregulation of proteins implicated in extracellular matrix, protein localisation/metabolism, KEAP1‐NFE2L2 pathway, lysosomes, carbohydrate metabolism, and transcriptional regulation. Kinase substrate enrichment analysis of phosphopeptides revealed potential role of kinases (CK2, CDK2, PKC, GSK3B) during this remodelling. We verified upregulated activity of casein kinase 2 (CK2) in secretome‐treated fibroblasts, and pharmacological CK2 inhibitor TBB (4,5,6,7‐Tetrabromobenzotriazole) significantly abrogated fibroblast activation and oxidative stress. Our data provides molecular insights into cardiomyocyte to cardiac fibroblast crosstalk, and the potential role of CK2 in regulating cardiac fibroblast activation and oxidative stress.


This work was supported by fellowships from Amelia Hains (David W. Greening) and the National Heart Foundation of Australia (David W. Greening: Vanguard 105072), Stafford Fox Medical Research Foundation (Shiang Y. Lim), and the Victorian Government's Operational Infrastructure Support Program. Bethany Claridge is supported by an Australian Government Training Program (RTP) scholarship and Baker Institute Bright Sparks Scholarship Top Up.


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Journal of Extracellular Biology





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© 2023 The Authors. Journal of Extracellular Biology published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.